1. Field of the Invention
The invention relates to certain aminomethyl derivatives of biologically active organic compounds useful as active ingredients in pharmaceutical compositions and methods of treatment.
2. The Prior Art
Intensive efforts have been undertaken recently in the area of enhancing the transport or delivery of drugs across such internal biological membranes as the blood-barrier, blood-testis barrier, etc. The functional barriers of the endothelial brain capillary wall (bloodbrain barrier) and the seminiferous tubule capillary wall (blood-testis barrier) seriously limit the transport or delivery of biologically active drug species to the brain and testis, respectively.
Prodrugs comprising derivatized or otherwise chemical and/or physically modified forms of the drug species have been designed which more readily penetrate these barriers. Upon transport across the membrane they are converted in situ to the active form whereupon they perform their intended biological function in the target organ. These prodrugs are also designed to resist metabolic conversions and other forms of degradation until they have crossed the barrier.
Considerable research has also been conducted in an attempt to solve the problem of enhancing the delivery of topically applied drugs across the topical skin membrane.
Many drugs have been found to be useful for the treatment of various skin disease states such as psoriasis and atopic dermatitis when they are given orally but are not effective when applied topically. However, the use of a drug in a topical manner to treat a topical disease state is desirable in that only a locally effective concentration of the drug needs to be attained in the skin. On the other hand, an oral dose develops a systemic (whole body) concentration of the drug. For example, 6-mercaptopurine (6-MP) is orally effective in the treatment of psoriasis but it is not effective topically. The oral dose of 6-MP is 150-250 mg/day, and, assuming complete absorption, produces a whole body burden of 6-MP of 150-250 mg/day. However, the skin, which is the site of the disease, comprises only 5% of the body and the psoriasis may involve only 10-20% of the skin. Thus, assuming uniform distribution of the drug from the oral dose, the topical dose would only have to be 1% to 0.5% of the oral dose. The net result of being able to deliver 1% to 0.5% of the oral dose locally (i.e., topically, at the site where its action is needed) would result in a tremendous decrease in the systemic toxicity associated with the use of the drug to treat psoriasis.
Although there are a large number of drugs that fall into the category described above, there are also a large number of drugs that are either marginally effective topically or else they are used in formulations that are irritating because of the incorporation into the formulation of so-called penetration enhancers and solubilizers. These marginally effective drugs would benefit from a transient chemical modification that would increase their solubility in milder, more acceptable (by the patient) formulations and would increase the partitioning of the drug (prodrug) into the skin. An example of such a drug is 5-fluorouracil (5-FU) which is conventionally used in a formulation containing propylene glycol (a solubilizer) and a penetration enhancer. The propylene glycol is very irritating to the skin and the course of treatment may last for several weeks.
Polar, high-melting, heterocyclic drugs which are relatively insoluble in lipids and in water have presented a challenge to pharmaceutical chemists for some time in their efforts to improve the topical (or oral) delivery of such agents so that they can be used effectively in clinical situations. One approach to meeting this challenge has been to use N-acyloxyalkyl prodrug derivatives which are lower-melting and more lipophilic than the parent drugs. Recently, a number of examples of the application of this approach to modifying heterocyclic drugs have been described (Bodor et al, U.S. Pat. No. 4,061,753; CA 87, 152278 (1977) and Sloan et al, Int. J. Pharm., 12, 299-313 (1982); Stella et al, U.S. Pat. No. 4,163,058; CA 91, 193312 (1979); Ozaki et al, U.S. Pat. No. 4,267,326; Mollgaard et al, Int. J. Pharm. 12, 153-162 (1982) and Sloan et al, J. Pharm. Sci., 72, 372-378 (1983).
Although no examples of prodrugs have been reported where both water and lipid solubility have been optimized in order to obtain enhanced delivery of drugs across topical membranes, there are a number of prodrugs which incorporate an amino group into the derivative and exhibit enhanced lipid solubility and dermal delivery (Sloan, U.S. Pat. No. 4,206,220; CA 93, 8017 (1980); Sloan and Little, CA, 96, 104087 (1982); Sloan, CA, 97, 144855 (1982) and Bodor et al, Int. J. Pharm. 10, 307-321 (1982).
Although the topical membrane or skin is a "biological membrane", it differs substantially from other membranes in that the barrier to absorption of drugs is the stratum corneum which comprises a dead, dry (5-10% H.sub.2 O), compact keratin-containing material. All other biological membranes comprise live, essentially aqueous (75-80% H.sub.2 O) material. Obviously, therefore, the considerations bearing on the live transport or delivery of drug species across other biological membranes are altogether different from those bearing on the delivery of drugs across the topical skin membrane.
A high degree of liphophilicity is necessary in any prodrug designed to effectively cross the skin membrane. The prodrug must substantially immediately convert to the parent active drug species after transport across the stratum corneum, however.
It has been suggested heretofore to employ certain N-Mannich type bases (referred to herein as aminomethyl derivatives) as prodrugs for oral or parenteral administration. See, for example, Pitman, Med. Res. Rev., Vol. 1, No. 2, pp. 189-214 (1981); Johansen et al, Arch. Pharm. Chemi., Sci. Ed. 8, 141-151, 207-214 (1980); Johansen et al, Arch. Pharm. Chemi. Sci. Ed. 10, 111-121 (1982); Bundgaard et al, Int. J. Pharm. 7, 119-127, 129-136 (1980); Bundgaard et al, J. Pharm. Sci., 69, No.1, 44-47 (1980); Bundgaard et al, Acta. Pharm., Suec. 18, 129-134 (1981); Bundgaard et al, Int. J. Pharm., 9, 7-16 (1981); Bundgaard et al, Int. J. Pharm., 8, 183-192 (1981); Bundgaard et al, Int. J. Pharm., 9, 7-16 (1981). There is no suggestion in the prior art, however, as to the utilization of such N-Mannich bases as topical prodrugs.
There is disclosed in U.S. Pat. No. 4,412,994 the use of Mannich-base hydroxamic acid prodrugs for topical administration to warm-blooded animals. The parent drugs from which the prodrugs are derived, however, are limited to "acyl residues of non-steroidal anti-inflammatory agents containing a carboxylic acid function".
The use of Mannich bases or aminomethyl derivatives for topical delivery involves the intact prodrug partitioning from a non-protic solvent (in which it is stable) into the skin (in which it is not stable because of the presence of water) where it reverts to the parent compound. On the other hand, the use of Mannich bases or aminomethyl derivatives for oral or parenteral use takes advantage of increased water solubility and increased dissolution properties of the derivatives to enhance the bioavilability of the parent drug, but it is the parent drug and not the prodrug that is actually involved in the partitioning from the aqueous environment (in which the prodrug is not stable) into the membranes and from there ultimately the systemic circulation. Thus, the topical delivery depends on the superior partioning properties of the intact prodrug while the oral or parenteral delivery still depends on partitioning properties of the parent drug and gains its only advantage from the more immediate and higher solution concentrations of the parent drug that develop from the use of the prodrugs.
It is an object of the present invention to provide novel aminomethyl derivatives of a class of biologically active organic compounds which function in a highly successful manner as topically applied prodrugs having an enhanced delivery or transport across the topical membrane.